1. Technical Field of the Invention
The present invention relates to the administration of an effective amount of at least one inhibitor of at least one calcium channel, or composition comprised thereof, for loosening/slackening and/or relaxing cutaneous and/or subcutaneous human skin tissue, in particular for treating/reducing skin wrinkles and fine lines.
2. Description of the Prior Art
Women, and even men, currently wish to appear youthful for as long as possible and consequently seek to eradicate the signs of aging of the skin, which are reflected, in particular, by wrinkles and fine lines. In this respect, the media and the fashion world extoll products intended to maintain for as long as possible skin which is radiant and wrinkle-free, which are signs of youthful skin, and all the more so since physical appearance favorably influences the psyche and/or the morale.
Heretofore, wrinkles and fine lines were treated using cosmetic products containing active agents acting on the skin, for example by moisturizing same or improving its cell renewal or, alternatively, by promoting the synthesis of collagen, of which skin tissue is composed. However, to date it is not known to reduce/treat wrinkles by intervening on the contractile elements present in the skin.
Thus, it is known that the-dermal muscles of the face are under the control of motor nerve afferences of the facial nerve and that, moreover, the interlobular septa of the hypoderm contain within them fibers which constitute a striated muscle tissue (panniculus carnosus). Moreover, it too is known that a sub-population of dermal fibroblasts, known as myofibroblasts, has contractile characteristics in common with muscle tissue.
Calcium is the final messenger of muscle contraction. The contraction-relaxation cycle is due to variations in the concentration of cytoplasmic calcium of from 10−8 to 10−5 M in the contractile cell.
In muscle at rest, the intracellular concentration of free calcium remains less than 10−8 M although the extracellular concentration is 10,000 times higher and although the force represented by the electrochemical potential gradient has a tendency to effect calcium penetration into the cell. This resting or quiescent state is due to the low permeability to calcium of the cell membrane and to the activity of various mechanisms which sequester calcium or expel it from the cell. Various cytoplasmic proteins, in particular parvalbumins, thus have the capacity to bind calcium. Among the intracellular organelles, the endoplasmic reticulum can accumulate and release calcium under conditions that are compatible with physiological regulations.
An increase in the level of calcium in the cytoplasm of the myocyte allows the activation of the contractile machinery. The influx of calcium into the intracellular compartment (depolarization) participates in decreasing the potential difference between the outside and the inside and thus renders the cell more excitable.
Specifically, the depolarization of the transverse tubules (invagination of the cell membrane) which propagates to the longitudinal tubules (sarcoplasmic reticulum) induces the momentary release of intracellular calcium by these tubules. In the presence of calcium, the contractile proteins of striated muscle have-an ATPase activity which provides the energy required for the contraction.
Conversely, the relaxation of striated muscle takes place when a new ATP molecule binds to the contractile proteins. The intracellular calcium then returns to the intracellular compartment and its concentration once again becomes close to a value of 10−8 M.
Moreover, it too has been shown that botulinum toxin, used originally to treat spasms, can act on states of muscular spasticity (see A. Blitzer et al., Arch. Otolaryngol. Head Neck Surg., 119, pages 1018 to 1022 (1993)), and on wrinkles of the glabella which are the wrinkles between the eyebrows (see J. D. Carruthers et al., J. Dermatol. Surg. Oncol., 18, pages 17 to 21 (1992)). Consequently, it is possible to affect the nerve component of wrinkles.
In the peripheral nervous system, the junction between a nerve and a muscle constitutes the neuro-muscular plaque, upstream of which is the efferent nerve pathway known as the motorneuron. Moreover, the cell membranes of each nerve fiber also comprise numerous ion channels, and in particular calcium ion channels, which are capable of allowing the corresponding element, which in this particular case is calcium, to traverse in ionic state.
The important role of calcium and of regulating its intracellular concentration in the phenomena of muscle contraction/relaxation can thus be readily appreciated.
Regulation of the intracellular concentration of calcium is only possible because the efflux of calcium corrects the influx. This can only be ensured by an expulsion of the cellular calcium via one or more mechanisms capable of overcoming the electrochemical potential gradient mentioned above.
Two types of mechanism can intervene: a calcium pump, which actively expels the cations at the expense of the hydrolysis of ATP, and a movement of calcium coupled to,a movement of sodium. In most cells, the ATP-dependent calcium pump operates more efficiently in the presence of calmodulin which increases its affinity.
In order best to describe the changes in permeability to calcium, it is currently common to consider that this permeability corresponds to the opening of membrane calcium channels, these channels being operated by variations in the membrane potential (VOC) or activation of membrane receptors (ROC). To date, six VOC types of calcium channels (L, N, T, P, Q and R) have been identified.
It is thus understood from the account hereinabove that the contraction or hypercontraction of certain facial muscles results in the appearance of wrinkles. This muscle activation is itself induced by a variation in the flow of calcium through transmembrane calcium channels.